Gail Simone is well known among the comic book community for coining the term Women in Refrigerators and writing the original list. She began a weekly column, entitled "You'll All Be Sorry!", which she updated regularly for two years. After scripting contributing several stories for The Simpsons, she entered superhero comics penning Deadpool and it's successor, Agent X, for fifteen issues. She began her five-year run on Birds of Prey with issue #56, and continued until issue #108, with a rotating team of artists.

When her long run on Birds of Prey was finished, she began an eight issue run on Action Comics with John Byrne, where she introduced Livewire into comic continuity. She subsequently wrote a six-issue miniseries called Villains United that tied heavily into the Infinite Crisis, and its sucessor, the six issue miniseries Secret Six.

With some ideas from Grant Morrison, Gail Simone invented the new Atom character, Ryan Choi. After eighteen issues, she left the title and started writing Wonder Woman from issue fourteen. Gail Simone teamed up with Nicola Scott again to write a new Secret Six ongoing series.

In 2010, after encouragement from DC Comics Chief Creative Officer and fellow writer, Geoff Johns, Simone relaunched Birds of Prey with artist Ed Benes who she had worked with previously on the first volume. She left Wonder Woman after the special 600th anniversary issue.

In 2011, Gail started DC's New 52 writing Batgirl and co-writing the Fury of Firestorm but left the latter after issue #6. She was the only female writer at DC Comics until the second wave.

In December 2012, she was apparently fired and informed that her time on Batgirl would end with issue #16. Simone was later informed that she would remain the Batgirl writer, with the full story behind the seemingly botched termination never revealed.

Around this time, she announced she would take up a second DC title: The Movement, while also going to do work for Dynamite's Red Sonja, her exclusive contract with DC having expiring.